Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor 1 is a mode of protein expression highly conserved from protozoa to mammals 2 . As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells 3 , 4 . We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c → g) at position −270 from the start codon of PIGM , a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.